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Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex

Chemical modifications of mRNA, the so-called epitranscriptome, represent an additional layer of post-transcriptional regulation of gene expression. The most common epitranscriptomic modification, N6-methyladenosine (m6A), is generated by a multi-subunit methyltransferase complex. We show that alpha...

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Autores principales: Jansens, Robert J.J., Verhamme, Ruth, Mirza, Aashiq H., Olarerin-George, Anthony, Van Waesberghe, Cliff, Jaffrey, Samie R., Favoreel, Herman W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347262/
https://www.ncbi.nlm.nih.gov/pubmed/35858564
http://dx.doi.org/10.1016/j.celrep.2022.111107
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author Jansens, Robert J.J.
Verhamme, Ruth
Mirza, Aashiq H.
Olarerin-George, Anthony
Van Waesberghe, Cliff
Jaffrey, Samie R.
Favoreel, Herman W.
author_facet Jansens, Robert J.J.
Verhamme, Ruth
Mirza, Aashiq H.
Olarerin-George, Anthony
Van Waesberghe, Cliff
Jaffrey, Samie R.
Favoreel, Herman W.
author_sort Jansens, Robert J.J.
collection PubMed
description Chemical modifications of mRNA, the so-called epitranscriptome, represent an additional layer of post-transcriptional regulation of gene expression. The most common epitranscriptomic modification, N6-methyladenosine (m6A), is generated by a multi-subunit methyltransferase complex. We show that alphaherpesvirus kinases trigger phosphorylation of several components of the m6A methyltransferase complex, including METTL3, METTL14, and WTAP, which correlates with inhibition of the complex and a near complete loss of m6A levels in mRNA of virus-infected cells. Expression of the viral US3 protein is necessary and sufficient for phosphorylation and inhibition of the m6A methyltransferase complex. Although m6A methyltransferase complex inactivation is not essential for virus replication in cell culture, the consensus m6A methylation motif is under-represented in alphaherpesvirus genomes, suggesting evolutionary pressure against methylation of viral transcripts. Together, these findings reveal that phosphorylation can be associated with inactivation of the m6A methyltransferase complex, in this case mediated by the viral US3 protein.
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spelling pubmed-93472622022-08-03 Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex Jansens, Robert J.J. Verhamme, Ruth Mirza, Aashiq H. Olarerin-George, Anthony Van Waesberghe, Cliff Jaffrey, Samie R. Favoreel, Herman W. Cell Rep Article Chemical modifications of mRNA, the so-called epitranscriptome, represent an additional layer of post-transcriptional regulation of gene expression. The most common epitranscriptomic modification, N6-methyladenosine (m6A), is generated by a multi-subunit methyltransferase complex. We show that alphaherpesvirus kinases trigger phosphorylation of several components of the m6A methyltransferase complex, including METTL3, METTL14, and WTAP, which correlates with inhibition of the complex and a near complete loss of m6A levels in mRNA of virus-infected cells. Expression of the viral US3 protein is necessary and sufficient for phosphorylation and inhibition of the m6A methyltransferase complex. Although m6A methyltransferase complex inactivation is not essential for virus replication in cell culture, the consensus m6A methylation motif is under-represented in alphaherpesvirus genomes, suggesting evolutionary pressure against methylation of viral transcripts. Together, these findings reveal that phosphorylation can be associated with inactivation of the m6A methyltransferase complex, in this case mediated by the viral US3 protein. 2022-07-19 /pmc/articles/PMC9347262/ /pubmed/35858564 http://dx.doi.org/10.1016/j.celrep.2022.111107 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Jansens, Robert J.J.
Verhamme, Ruth
Mirza, Aashiq H.
Olarerin-George, Anthony
Van Waesberghe, Cliff
Jaffrey, Samie R.
Favoreel, Herman W.
Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex
title Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex
title_full Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex
title_fullStr Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex
title_full_unstemmed Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex
title_short Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex
title_sort alphaherpesvirus us3 protein-mediated inhibition of the m6a mrna methyltransferase complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347262/
https://www.ncbi.nlm.nih.gov/pubmed/35858564
http://dx.doi.org/10.1016/j.celrep.2022.111107
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